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Metabolism of Cyclic-Di-GMP in Bacterial Biofilms: from a General Overview to Biotechnological Applications

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Metabolism of Cyclic-Di-GMP in Bacterial Biofilms: from a General Overview to Biotechnological Applications Indian Journal of Biotechnology Vol 10, October 2011, pp 423-431 Metabolism of cyclic-di-GMP in bacterial biofilms: From a general overview to biotechnological applications Nicoletta Castiglione 1, Valentina Stelitano 1, Serena Rinaldo 1, Giorgio Giardina 1, Manuela Caruso 1 and Francesca Cutruzzolà 1,2* 1Department of Biochemical Sciences "A. Rossi Fanelli”, Sapienza University of Rome, Rome, Italy 2Consorzio I.N.B.B., 00136 Rome, Italy Bacteria exist in nature in a planktonic single-cell state or in a sessile multicellular state, the biofilm. In the latter state, the bacterial community optimizes the cell-environment and cell to cell communication strategies. Biofilms are widely diffuse in many industrial, environmental and clinical settings and are less sensitive to treatments with antimicrobial agents compared to planktonic cells. Biofilms formed by bacterial pathogens, such as, those formed by Pseudomonas aeruginosa in immunocompromised patients, have a high impact on public health. The switch between the planktonic and the biofilm lifestyle is strictly regulated by the second messenger 3', 5'-cyclic diguanylic acid (c-di-GMP). The intracellular levels of this molecule are controlled by two classes of enzymes: diguanylate cyclases (DGC) and phosphodiesterases (PDE). In this review, we report the structural and functional data available to date on these enzymes and we summarize the possible medical, environmental and industrial biotechnological applications involving bacterial c-di-GMP metabolism. Keywords: Biofilm, cyclic-di-GMP, inhibitors, pathogenesis, PDE, DGC Introduction The present review has focused on the human Bacteria are able to communicate and behave like a pathogen Pseudomonas aeruginosa , a well-known multicellular organism forming biofilm, a highly model organism and one of the most important organized structure consisting of cells embedded bacteria forming biofilms. Since the enzymes within a matrix of extracellular polymeric substance involved in 3',5'-cyclic diguanylic acid (c-di-GMP) (EPS) attached to a surface. As a matter of fact, synthesis and degradation are found in the bacterial cells exist in nature in a planktonic single- majority of known bacterial species 8, the information cell state or in a sessile multicellular state of the reported here is relevant for other important biofilms1. Biofilms are abundant in many industrial, pathogens. environmental and clinical settings, such as, food P. aeruginosa is an opportunistic human processing environments, potable water and medical pathogen, a leading cause of both community and devices 2,3. In particular, bacterial biofilms found on hospital acquired infections (13% of all nosocomial the surface of medical devices are a major cause of infections). P. aeruginosa biofilm is the major hospital-associated infections 4,5. Moreover, biofilms cause of death in patients of cystic fibrosis (CF), formed by pathogens play an important role in the a genetic disease affecting 1/2500 newborns in infection of living tissues and are responsible for the 9 Europe . In the CF lung, environment is poor resistance to antibiotics and to the host immune of oxygen and rich of nitrate, and under these system 2,6. Bacteria growing as microbial community conditions, P. aeruginosa is able to survive, are less sensitive to treatments with antimicrobial thanks to its anaerobic metabolism 6,10,11 , causing agents compared to planktonic cells 1,6 and produce chronic infections 10 . The bacterium is intrinsically many virulence factors 7. According to the Centers resistant to a wide array of antibiotics. Moreover, for Disease Control and Prevention (USA), 65% of it is prone to acquire new resistance genes all infections in developed countries are caused through horizontal gene transfer and produces an by biofilms. impressive array of virulence factors. The low ————— efficacy of existing therapies in eradicating *Author for correspondence: Tel: 0039-0649910713; Fax: 0039-064440062 P. aeruginosa infection calls for the development of E-mail: [email protected] new therapeutic options. 424 INDIAN J BIOTECHNOL, OCTOBER 2011 The Second Messenger 3 ′′′, 5 ′′′ Cyclic Diguanylic 5'-pGpG or GMP as products (Fig. 1). DGCs are Acid (C-di-GMP) and Its Turnover often called GGDEF proteins due to the conserved During biofilm formation, the pattern of gene amino acids found in their active site; unlikely expression is changed with respect to planktonic other bacterial domains, the GGDEF domain is cells and new intracellular signalling pathways are completely absent in eukaryotes 17 . The presence of activated. Therefore, biofilm formation can be viewed putative DGCs only in bacteria suggests that these as a developmental process 3, regulated by the key enzymes are excellent candidates for the development signal molecule c-di-GMP. This second messenger of anti-bacterial compounds. controls in bacteria an array of cellular processes Based on conserved sequence signatures, PDEs linking environmental sensing with sessile-motile are also grouped into the EAL and HD-GYP 18 transition 12,13 (Fig. 1). The clearest role for c-di-GMP families . The large number of GGDEF and EAL is, indeed, its ability to regulate the decision to switch domain proteins in a single species is somewhat 13 from a free-swimming bacterium to a surface-attached puzzling . In general, Gram-positive bacteria have bacterium 14 , determining the timing and amplitude less of DGC/PDE proteins than Gram-negative of complex processes like motility, cell adhesion, bacteria. By contrast, proteins containing the HD- biofilm formation and differentiation 15 . A low GYP domain are less common or even absent in concentration of c-di-GMP is associated with flagellar some species, whereas in other species, such as, 16 Thermotoga maritima , they account for all PDE motors or retracting pili , whereas an high amount 19,20 favours the expression of adhesins and EPS, finally activity in the cell . The number of putative DGCs leading to biofilm formation and pathogenicity 15 . and PDEs encoded in individual bacterial genomes is The exceptional importance of c-di-GMP in bacterial highly variable (for example over 29 in Escherichia physiology and pathogenesis has been recently coli , 14 in Caulobacter crescentus , 60 in Vibrio acknowledged in a commentary published in the cholerae , 41 in P. aeruginosa and none in prestigious journal Cell 14 . Helicobacter pylori ), this may reflect the ability to C-di-GMP is synthesized by the enzyme survive in different environmental niches. GGDEF diguanylate cyclase (DGC) starting from two and EAL domains are often found in tandem guanosine triphosphate (GTP) molecules and within the same protein; these hybrid proteins its degradation is mediated by specialized frequently show only one enzymatic activity with the phosphodiesterases (PDE) that yield the linear catalytically inactive domain, potentially serving a regulatory function 15 . Most DGCs and PDEs are also associated with known or hypothetical signal input domains (globin-like, PAS/PACM, GAF, HAMP, CHASE4 or membrane sensory domains MHYT or MASE1) 17 , putatively involved in sensing a range of environmental signals (oxygen, blue light, nutrient starvation, antibiotics, etc). Little is known on the intracellular receptors of c-di-GMP, which convert the increase/decrease of c-di-GMP into a biological response. Possible c-di-GMP-sensing domains include the PilZ, BcsA or PelD domains 12,21,22 , the GGDEF/EAL containing hybrid proteins 23 and even riboswitches 24 . How the DGCs and PDEs function together to produce a coherent output signal is still unclear; different c-di-GMP circuits could be separate in time and in space through 15 compartmentalization . Fig. 1—Cyclic-di-GMP turnover: Cyclic-di-GMP synthesis and degradation are, respectively, controlled by two classes of In the P. aeruginosa , PAO1 genome presents 41 enzymes, diguanylate cyclases (DGC), characterized by a GGDEF ORFs containing putative DCG (GGDEF) and/or PDE domain, and phosphodiesterases (PDE), characterized by an EAL (EAL or HD-GYP) genes (Table 1). Insertional mutants or a HD-GYP domain. Cyclic-di-GMP controls many cellular processes like motility, virulence, biofilm formation and in the DGC or DGC-PDE genes show an effect, either 25,26 differentiation 12 . reducing or increasing biofilm formation . CASTIGLIONE et al : CYCLIC-DI-GMP METABOLISM AND BIOFILM TREATMENT 425 Table 1—Genes involved in c-di-GMP turnover in P. aeruginosa PAO1 PAO1 Predicted domains Size (AA) PAO1 Predicted domains Size code code (AA) DGC (GGDEF domain: 2GTP --> c-di-GMP) PA0169 GGDEF 235 PA3177 GGDEF 307 PA0290 PAC-GGDEF 323 PA3343 TM-TM-TM-TM-TM-GGDEF 389 PA0338 PAC-GGDEF 376 PA3702 ResponseReg.-GGDEF 347 (WspR) PA0847 TM-CHASE4-TM- HAMP-PAS-PAC- 735 PA4332 TM-TM-TM-TM-TM-GGDEF 487 GGDEF PA1107 TM-TM-TM-TM-TM-GGDEF 398 PA4396 ResponseReg. -GGDEF 366 PA1120 TM- HAMP-GGDEF 435 PA4843 ResponseReg .-GGDEF 542 (TpbB) PA1851 TM-TM-TM-TM-TM-GGDEF 401 PA4929 7TMR-DISMED2-GGDEF 680 PA2771 GAF-GGDEF 341 PA5487 GGDEF 671 PA2870 GGDEF 525 Hybrid proteins (GGDEF + EAL domains) PA0285 TM-TM-PAS-PAC-PAS-PAC-GGDEF- 760 PA3258 EAL-CBS-GGDEF 601 EAL PA0575 TM-SPB_BAC_3-TM-PAS-PAC-PAS- 1245 PA3311 TM- MHYT- MHYT- MHYT- 783 PAC-PAS-PAC-PAS-PAC-GGDEF-EAL GGDEF-EAL PA0861 TM-TM-PAS-GGDEF-EAL 818 PA4367 TM-TM- GGDEF-EAL 687 (BifA) PA1181 MASE1-PAS-PAC-PAS-PAC-GGDEF- 1120 PA4601 TM-TM-PAS-PAC-PAS-PAC-PAS- 1415 EAL (MorA) PAC-GGDEF-EAL PA1433 TM- HAMP-GGDEF-EAL 650 PA4959 ResponseReg .- GGDEF-EAL 691 (FimX) PA1727 TM-TM-
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